Simple sugar delays neurodegeneration caused by enzyme deficiency

June 20, 2018, Baylor College of Medicine
Dr. Marco Sardiello. Credit: Baylor College of Medicine

A new therapeutic approach may one day delay neurodegeneration typical of a disease called mucopolysaccharidoses IIIB (MPS IIIB). Neurodegeneration in this condition results from the abnormal accumulation of essential cellular molecules called mucopolysaccharides. Looking to find alternative therapeutic strategies for this rare genetic disease, a team of researchers investigated whether enhancing the cells' ability to clear accumulation of cellular waste would help eliminate the abnormal storage of mucopolysaccharides. They report in the journal Autophagy that the sugar trehalose increases cellular waste disposal and improves the neurological symptoms in a mouse model of the disease.

"MPS IIIB is one of about 50 characterized by the accumulation of material inside tiny cellular sacs called lysosomes," said corresponding author Dr. Marco Sardiello, assistant professor of molecular and human genetics and a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor College of Medicine. "In the case of MPS IIIB, a mutation on a gene that codes for a lysosomal enzyme that breaks down a cellular material called , renders the enzyme ineffective. Consequently, the lysosome cannot do its work of degrading heparan sulfate to either discard it or recycle it, and the material accumulates."

Over the years, accumulation of heparan sulfate in lysosomes leads to degeneration of brain tissue. Although infants appear healthy at first, they slowly begin to show behavioral problems, hyperactivity, aggressiveness, sleep disturbances and loss of vision and hearing. Later in life, they become immobile and develop swallowing difficulties. Usually, they don't live past the second decade. Current strategies being tested for the treatment of this condition in animal models include attempting to correct the enzyme deficiency by providing a fully working enzyme. However, this approach faces challenges such as having limited ability to cross the blood-brain barrier and reaching the brain areas where the enzyme is needed.

A non-traditional approach

"We explored a way to treat this condition with a nontraditional approach," Sardiello said. "We recently discovered that the small sugar promotes the recycling of cellular waste. This made us think of an indirect approach to try to solve the accumulation of heparan sulfate. Instead of correcting the , we would try to overcome it by enhancing the cells' natural ability to discard cellular waste."

The researchers tested their approach on a mouse model of MPS IIIB. These mice have a mutation that results in the recapitulation of most of the clinical symptoms observed in patients, including progressive neurodegeneration, loss of vision, brain inflammation and shorter lifespan.

One group of MPS IIIB mice received trehalose in the drinking water, while another group of MPS IIIB mice did not receive the sugar. As controls, normal mice without the mutation were provided water with or without trehalose. The researchers observed the animals for 11 months, taking samples at the middle and at the end of the observation period.

"The results were highly encouraging," said first author Dr. Parisa Lotfi, postdoctoral associate in the Sardiello lab. "The MPS IIIB mice treated with trehalose lived longer, improved their hyperactive behavior and delayed several neuropathological features, most notably the , when compared with MPS IIIB mice not treated with trehalose."

In addition, the researchers explored the molecular mechanism underlying the trehalose effect.

"Previously, we had discovered that trehalose activates TFEB, a master regulator of the lysosomal system. As the activity of TFEB increases, the degradation and clearance of molecules in the lysosomes becomes more efficient," said Lotfi. "Here, we were the first to quantify the amount of trehalose that crosses the blood-brain barrier and activates TFEB in the brain. In turn, TFEB activated the lysosomal system, which led to enhanced clearance of material accumulation, reduced neuroinflammation, retinal degeneration and vision loss and extended lifespan."

This study is the first to show that trehalose is acting through TFEB but no other molecules. Also, this is the first preclinical study showing that it is possible to delay retinal degeneration and loss of vision in a of MPS IIIB.

"The effect on the retina is important," Lotfi said. "Loss of vision is one of the most devastating aspects of some lysosomal diseases. In animal models, treatments based on enzyme replacement therapy do not reach the brain and do not counteract loss of vision. We think that in the future our strategy can potentially be used either as the main therapy or complementary to other therapies."

"Our results encourage us to consider that trehalose also may be effective in other lysosomal storage diseases, such as Batten disease," Sardiello said. "Trehalose is a widely used food additive with no current restrictions for human use."

Explore further: Research reveals strategy to potentially treat juvenile Batten disease

More information: Parisa Lotfi et al, Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency, Autophagy (2018). DOI: 10.1080/15548627.2018.1474313

Related Stories

Research reveals strategy to potentially treat juvenile Batten disease

February 6, 2017
Researchers at Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and King's College London have discovered a treatment that improves the neurological symptoms in a ...

Study holds hope of a treatment for deadly genetic disease, MPS IIIB

September 29, 2014
MPS IIIB is a devastating and currently untreatable disease that causes progressive damage to the brain, leading to profound intellectual disability, dementia and death—often before reaching adulthood.

Type of sugar may treat atherosclerosis, mouse study shows

June 7, 2017
Researchers have long sought ways to harness the body's immune system to treat disease, especially cancer. Now, scientists have found that the immune system may be triggered to treat atherosclerosis and possibly other metabolic ...

Biochemists confirm existence of theoretical genetic disorder

January 8, 2018
Thanks to the sequencing of the human genome, scientists can now discover potential disorders for which there are no known patients. One such disorder is MPS III-E, originally also called Dierks's disorder after its discoverer. ...

Photoreceptor cell death leads to blindness in CLN5 form of Neuronal Ceroid Lipofuscinosis

May 16, 2017
Researchers from the University of Eastern Finland have discovered a likely cause for visual impairment and eventual loss of vision in the Finnish variant of Neuronal Ceroid Lipofuscinosis (NCL). Visual impairment associated ...

Recommended for you

RNAi therapy mitigates preeclampsia symptoms

November 19, 2018
A collaboration of scientists from the University of Massachusetts Medical School, Beth Israel Deaconess Medical Center and Western Sydney University, have shown that an innovative new type of therapy using small interfering ...

Mutation that causes autism and intellectual disability makes brain less flexible

November 19, 2018
About 1 percent of patients diagnosed with autism spectrum disorder and intellectual disability have a mutation in a gene called SETD5. Scientists have now discovered what happens on a molecular level when the gene is mutated ...

Widely used reference for the human genome is missing 300 million bits of DNA

November 19, 2018
For the past 17 years, most scientists around the globe have been using the nucleic acid sequence, or genome, an assembly of DNA information, from primarily a single individual as a kind of "baseline" reference and human ...

Skeletal imitation reveals how bones grow atom-by-atom

November 19, 2018
Researchers from Chalmers University of Technology, Sweden, have discovered how our bones grow at an atomic level, showing how an unstructured mass orders itself into a perfectly arranged bone structure. The discovery offers ...

Signal peptides' novel role in glutamate receptor trafficking and neural synaptic activity

November 19, 2018
Glutamate is the major excitatory neurotransmitter in the brain, and the postsynaptic expression level of glutamate receptors is a critical factor in determining the efficiency of information transmission and the activity ...

A molecule for fighting muscular paralysis

November 19, 2018
Myotubular myopathy is a severe genetic disease that leads to muscle paralysis from birth and results in death before two years of age. Although no treatment currently exists, researchers from the University of Geneva (UNIGE), ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.